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Review of hepatocyte transplantation

  • Topics
  • HBP treatment using cell transplantation in the near future
  • Published:
Journal of Hepato-Biliary-Pancreatic Surgery

Abstract

Background

Hepatocyte transplantation is a promising treatment for several liver diseases and can also be used as a “bridge” to liver transplantation in cases of liver failure. Although the first animal experiments with this technique began in 1967, it was first applied in humans only in 1992. Unfortunately, unequivocal evidence of transplanted human hepatocyte function has been obtained in only one patient with Crigler–Najjar syndrome type I and, even then, the amount of bilirubin–UDP-glucuronosyltransferase enzyme activity derived from the transplanted cells was not sufficient to eliminate the patient’s eventual need for organ transplantation.

Methods

A literature review was carried out using MEDLINE and library searches.

Results

This review considers the following: (1) alternatives or bridges to orthotopic liver transplantation (OLT); (2) solutions to the shortage of organs—the shortage of organ donors has impeded the development of human hepatocyte transplantation, and immortalized hepatocytes in particular could provide an unlimited supply of transplantable cells in a nearly future; (3) future directions. We review these efforts along with hepatocyte transplantation over the last 13 years.

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References

  1. Demetrious AA, Levenson SM, Novikoff PM, Novikovv AB, Chowdhury NR, Whiting J, et al. Survival, organization, and function of microcarrier-attached hepatocytes transplanted in rats. Proc Natl Acad Sci USA. 1986;83:7475–9.

    Article  Google Scholar 

  2. Sutherland DER, Numate M, Matas AJ, Simmons RL, Najaran JS. Hepatocellular transplantation in acute liver failure. Surgery. 1977;82:124–32.

    PubMed  CAS  Google Scholar 

  3. Makowka L, Rotstein LE, Falk RE, Falk JA, Langer B, Nossal NA, et al. Reversal of toxic and anoxic induced hepatic failure by syngeneic, allogeneic, and xenogeneic hepatocyte transplantation. Surgery. 1980;88:244–53.

    PubMed  CAS  Google Scholar 

  4. Arkadopoulos N, Chen SC, Khalili TM, Detry O, Jewitt WR, Lila H, et al. Transplantation of hepatocytes for prevention of intracranial hypertension in pigs with ischemic liver failure. Cell Transplant. 1998;7:357–63.

    Article  PubMed  CAS  Google Scholar 

  5. Ribeiro J, Nordlinger B, Ballet F, Cynober L, Coudray-Lucas C, Baudrimont M, et al. Intrasplenic hepatocellular transplantation corrects hepatic encephalopathy in portacaval-shunted rats. Hepatology. 1992;15:12–8.

    Article  PubMed  CAS  Google Scholar 

  6. Rugstad H, Robinson S, Yamoni C, Tashjian AJ. Transfer of bilirubin uridine-5-disphosphate-glucuronyltransferase to enzyme deficient rats. Science. 1970;170:553–5.

    Article  PubMed  CAS  Google Scholar 

  7. Wiederkehr J, Kondos G, Pollak R. Hepatocyte transplantation for the low-density lipoprotein receptor-deficient state. A study in the Watanabe rabbit. Transplantation. 1990;50:466–71.

    Article  PubMed  CAS  Google Scholar 

  8. Fox IJ, Roy Chowdhury J, Kaufman S, Goertzen T, Roy Chowdhury N, Warkentin P, et al. Treatment of Crigler–Najjar syndrome type I with hepatocyte transplantation. N Engl J Med. 1998;338:1422–6.

    Article  PubMed  CAS  Google Scholar 

  9. Tada K, Roy-Chowdhury N, Prasad V, Kim BH, Manchikalapudi P, Fox IJ, et al. Long-term amelioration of bilirubin glucuronidation defect in Gunn rats by transplanting genetically modified immortalized autologous hepatocytes. Cell Transplant. 1998;7:607–16.

    Article  PubMed  CAS  Google Scholar 

  10. Schumacher IK, Okamoto T, Kim BH, Chowdhury NR, Chowdhury JR, Fox IJ. Transplantation of conditionally immortalized hepatocytes to treat hepatic encephalopathy. Hepatology. 1996;24:337–43.

    Article  PubMed  CAS  Google Scholar 

  11. Cai J, Ito M, Westerman K, Kobayashi N, Leboulch P, Fox I. Construction of a non-tumorigenic rat hepatocyte cell line for transplantation: reversal of hepatocyte immortalization by site-specific excision of the SV40 T antigen. J Hepatol. 2000;33:701–8.

    Article  PubMed  CAS  Google Scholar 

  12. Westerman KA, Leboulch P. Reversible immortalization of mammalian cells mediated by retroviral transfer and site-specific recombination. Proc Natl Acad Sci USA. 1996;93:8971–6.

    Article  PubMed  CAS  Google Scholar 

  13. Nakamura J, Okamoto T, Schumacher IK, Tabei I, Chowdhury NR, Chowdhury JR, et al. Treatment of surgically induced acute liver failure by transplantation of conditionally immortalized hepatocytes. Transplantation. 1997;63:1541–7.

    Article  PubMed  CAS  Google Scholar 

  14. Ito M, Ito R, Yoshihara D, Ikeno M, Kamiya M, Suzuki N, et al. Immortalized hepatocytes using human artificial chromosome. Cell Transplant. 2008;17(1–2):165–71.

    Article  PubMed  Google Scholar 

  15. Afzelius BA, Schoental R. The ultrastructure of the enlarged hepatocytes induced in rats with a single oral dose of retrorsine, a pyrrolizidine (Senecio) alkaloid. J Ultrastruct Res. 1967;20(5):328–45.

    Article  PubMed  CAS  Google Scholar 

  16. Mito M, Kusano M, Kawaura Y. Hepatocyte transplantation in man. Transplant Proc. 1992;24(6):3052–3.

    PubMed  CAS  Google Scholar 

  17. Mito M, Kusano M, Ohnishi T, Saito T, Evata H. Hepatocellular transplantation–morphological study on rat hepatocytes transplanted into rat spleen. Gastroenterol Jpn. 1978;13:480–90.

    PubMed  CAS  Google Scholar 

  18. Ito M, Nagata H, Yamamoto T, Yoshihara D, Fox IJ, Miyakawa S. Intrasplenic hepatocyte transplantation prolonged the survival in Nagase analbuminemic rats with liver failure induced by common bile duct ligation. Cell Transplant. 2007;16(5):547–53.

    PubMed  Google Scholar 

  19. Nagata H, Ito M, Shirota C, Edge A, McCowan TC, Fox IJ. Route of hepatocyte delivery affects hepatocyte engraftment in the spleen. Transplantation. 2003;76(4):732–4.

    Article  PubMed  Google Scholar 

  20. Kobayashi N, Ito M, Nakamura J, Cai J, Hammel JM, Fox IJ. Treatment of carbon tetrachloride and phenobarbital-induced chronic liver failure with intrasplenic hepatocyte transplantation. Cell Transplant. 2000;9(5):671–3.

    PubMed  CAS  Google Scholar 

  21. Kobayashi N, Ito M, Nakamura J, Cai J, Cao C, Hammel JM, et al. The role of hepatocyte transplantation to treat chronic liver failure. Transplant Proc. 2000;32(7):2287–8.

    Article  PubMed  CAS  Google Scholar 

  22. Kobayashi N, Ito M, Nakamura J, Cai J, Hammel JM, Fox IJ. Hepatocyte transplantation improves liver function and prolongs survival in rats with decompensated liver cirrhosis. Transplant Proc. 1999;31(1–2):428–9.

    Article  PubMed  CAS  Google Scholar 

  23. Platt J. New directions for organ transplantation. Nature. 1998;392:11–7.

    Article  PubMed  CAS  Google Scholar 

  24. Ramirez P, Chavez R, Majado M, Munitiz V, Munoz A, Hernandez Q, et al. Life-supporting human complement regulatory decay accelerating factor transgenic pic liver xenograft maintains the metabolic function and coagulation in the nonhuman primate for up to 8 days. Transplantation. 2000;70:989–98.

    Article  PubMed  CAS  Google Scholar 

  25. Ito M, Nagata H, Cai J, Edge AS, Platt JL, Fox IJ. Treatment of cirrhosis and liver failure in rats by hepatocyte xenotransplantation. Gastroenterology. 2003;124(2):422–31.

    Article  PubMed  Google Scholar 

  26. Jo D, Nashabi A, Doxsee C, Lin Q, Unutmaz D, Chen J, et al. Epigenetic regulation of gene structure and function with a cell-permeable Cre recombinase. Nat Biotechnol. 2001;10:929–33.

    Article  CAS  Google Scholar 

  27. Ito M, Cai J, Nagata H, Westerman KA, Lafleur D, Chowdhury JR, et al. Treatment of liver failure in rats with end-stage cirrhosis by transplantation of immortalized hepatocytes. Hepatology. 2002;36(2):386–94.

    Article  PubMed  CAS  Google Scholar 

  28. Zhang Y, Riesterer C, Ayrall A, Sablitzky F, Littlewood TD, Reth M. Inducible site-directed recombination in mouse embryonic stem cells. Nucleic Acids Res. 1996;24:543–8.

    Article  PubMed  CAS  Google Scholar 

  29. Berry M, Friend D. High yield preparation of isolated rat liver parenchymal cells: a biochemical and fine structural study. J Cell Biol. 1969;43:506–20.

    Article  PubMed  CAS  Google Scholar 

  30. Seglen P. Preparation of isolated rat liver cells. Methods Cell Biol. 1976;13:29–83.

    Article  PubMed  CAS  Google Scholar 

  31. Conjeevaram HS, Nagle A, Katz A, Kaminsky-Russ K, McCullough AJ, Mullen KD. Reversal of behavioral changes in rats subjected to portacaval shunt with oral Neomycin therapy. Hepatology. 1994;19:1245–50.

    Article  PubMed  CAS  Google Scholar 

  32. Blei AT, Olafsson S, Therrien G, Butterworth RJ. Ammonia-induced brain edema and intracranial hypertension in rats after portacaval shunt. Hepatology. 1994;19:1437–43.

    PubMed  CAS  Google Scholar 

  33. Kobayashi N, Ito M, Nakamura J, Cai J, Gao C, Hammel J, et al. Hepatocyte transplantation in rats with decompensated cirrhosis. Hepatology. 2000;31:851–7.

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Department of Surgery, Fujita-Health University, Toyoake, Aichi, Japan

    Masahiro Ito, Hideo Nagata & Shuichi Miyakawa

  2. Department of Surgery, University of Nebraska Medical Center, Omaha, NE, USA

    Ira J. Fox

Authors
  1. Masahiro Ito
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  2. Hideo Nagata
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  3. Shuichi Miyakawa
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  4. Ira J. Fox
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Corresponding author

Correspondence to Masahiro Ito.

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Ito, M., Nagata, H., Miyakawa, S. et al. Review of hepatocyte transplantation. J Hepatobiliary Pancreat Surg 16, 97–100 (2009). https://doi.org/10.1007/s00534-008-0023-0

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  • DOI: https://doi.org/10.1007/s00534-008-0023-0

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